CRF-SKIRBALL Interventional Innovation Corner

Intervention in Heart Failure

The Skirball Center for Innovation (SCI) at the Cardiovascular Research Foundation (CRF) Interventional Innovation Corner is headed by section editor Juan F. Granada, MD, Executive Director and Chief Innovation Officer; Assistant Professor of Medicine, Columbia University College of Physicians and Surgeons, New York City, New York.

The Skirball Center for Innovation (SCI) at the Cardiovascular Research Foundation (CRF) Interventional Innovation Corner is headed by section editor Juan F. Granada, MD, Executive Director and Chief Innovation Officer; Assistant Professor of Medicine, Columbia University College of Physicians and Surgeons, New York City, New York.

Section Editor Juan F. Granada, MD

A discussion with heart failure specialist Daniel Burkhoff, MD, PhD, Director of Heart Failure, Hemodynamics and Circulatory Support, CRF Clinical Trials Center; Adjunct Associate Professor, Columbia University, New York, New York.

Introduction 

Juan F. Granada, MD

Interventional heart failure is a field that has been growing very fast over the last decade. It has been around for quite some time, particularly with the development of left ventricular assist devices (LVADs), but as catheter-based technologies mature, a great deal of interest has arisen in developing devices to monitor and treat patients with heart failure. Heart failure has multiple phenotypes, ranging from patients who have normal ejection fractions to patients with end-stage systolic dysfunction requiring heart transplant. There is a wide variety of conditions and patients, and the overall population is among the largest of all cardiovascular diseases. There are several devices now under development to treat heart failure with interventional methods, as well as continuing work on the development of sensors to monitor the pressures inside the cardiac chambers. Currently, all heart failure patients are treated with medications and, when symptoms persist, we turn to devices to further improve patient quality of life. Several companies are developing device-based options for patients who are symptomatic but not truly end stage, such as technologies for remote patient monitoring to optimize medical therapies. 

To learn more about this amazing field and the innovations to come, we talked with heart failure specialist Daniel Burkhoff, MD, PhD, Director of Heart Failure, Hemodynamics and Circulatory Support, CRF Clinical Trials Center; Adjunct Associate Professor, Columbia University, New York, New York.

Dr. Burkhoff, can you describe the heart failure population and the challenges we face with this disease?

The heart failure population is very diverse, including patients that span a very wide range of symptoms and degrees of left ventricular dysfunction. And, over the last 10 to 15 years, it has become clear that the severity of symptoms does not necessarily relate to the degree of left ventricular dysfunction. So, at the one extreme, we have patients who have recognized left ventricular dysfunction, but are relatively asymptomatic. On the other extreme, we have patients who have normal left ventricular function and are highly symptomatic. This emphasizes the fact that heart failure is a clinical syndrome characterized by effort intolerance and that there are many factors, both cardiac and non-cardiac, that can result in heart failure. It is a syndrome that is more complex than originally appreciated. In the population with compromised LV function, what we call reduced ejection fraction (EF) heart failure (HFrEF), medications are very effective for a majority of patients. The challenge we face is for the smaller percentage, say 20-30%, where the medications have really run their course and patients are left with quite a lot of symptoms. For those patients, we turn towards devices to either improve their heart function or that are helpful in optimizing medical therapies. For the group of patients with preserved EF, so-called HFpEF patients, there are no proven medications. There have been multiple failed clinical trials looking at different medications and there are several ongoing trials looking at other medications, but also, now we are starting to investigate various device options for this population as well. Current research has shown that the HFpEF population is comprised of a very diverse group of patients, which, in part, may have contributed to the seemingly slow progress finding solutions for these patients.

Why might someone have preserved LV function but show symptoms of heart failure?

Originally, in decades past, it was thought that these patients had what was called “diastolic heart failure.” It has now been increasingly recognized that diastolic heart failure is probably not the cause of symptoms in a majority of these patients. There are a host of issues that contribute to a volume overload state, which is really what these patients suffer from. Comorbid conditions such as hypertension, diabetes, impaired renal function, obesity, sedentary lifestyle, and peripheral deconditioning all appear to be important contributing factors that contribute to abnormal metabolism of salt and water that lead to increases in central and peripheral pressures, and these pressures rise dramatically even with minimal levels of exercise. So, it has turned out to be a complex and diverse disease with many potential underlying causes that result in a similar clinical syndrome. Weeding out, in a particular patient, what the contributing factors are has not really been solved at this point.

What do you envision as the future role of the heart failure specialist?

Heart failure specialists are becoming an increasingly sought-after specialty, because heart failure patients require a lot of medical attention. There are now 4 or 5 different drugs that HFrEF patients should be on, and to be effective, the introduction of these drugs needs to be timed properly and the doses need to be optimized. Then, as the patients start failing, diagnostics, as well as the triage of the patients to different types of device therapies are becoming increasingly more complex. It really opens the door for more specialists in the field. While the heart failure specialists are busy titrating drugs and doing tests to ensure that there are no identifiable and treatable causes of the heart failure, as we discussed, we are also looking at new options for device-based treatments. Many available devices are implanted by interventional cardiologists and electrophysiologists. The more invasive devices, primarily durable left ventricular assist devices, are implanted by surgeons. You can think of the heart failure patient as coupled with his/her heart failure specialist at the center of a healthcare network. The patient/physician interact with diagnosticians and physicians within the network who administer therapeutic devices. For example, echocardiographers and nuclear cardiologists play a critical role in quantifying and tracking changes in LV function, valve lesions, and looking for viable myocardium. Such information is used for decisions about whether revascularization, valve repair/replacement, implantable defibrillator, cardiac resynchronization therapy, or other devices are indicated. It is the heart failure cardiologist that is primarily responsible for coordinating this care and making the final decisions about which therapies are to be recommended.

Currently, the interventional cardiologists don’t play a huge role in heart failure treatment, but I think this is probably the area that will show the most growth in heart failure in the next decade. This is because of the increasing role of interventional cardiologists in delivering therapies. Transcatheter aortic valve replacement (TAVR) is an example. Although it doesn’t overlap a huge amount with the heart failure population, new studies are examining the role of TAVR in supposedly asymptomatic patients with LV dysfunction. As we start moving into percutaneous mitral valve repair and replacement, especially for functional mitral regurgitation (MR), this is almost exclusively an HFrEF population. It is one example of the next wave of interaction between heart failure and interventional cardiologists. This cross-discipline cooperation is reflected in some of the current clinical trials of percutaneous mitral valve repair, which include co-principal investigators from the interventional cardiology community and from the heart failure community. There are other potential therapies that are under investigation both in and outside of the U.S. that are focused on the interventional cardiologist. There is every reason to believe that this will be the next large growth area for interventional cardiology. 

Let’s talk more about innovation in devices oriented toward heart failure patients:

a) Implantable diagnostics

Implantable diagnostics are one of the most recent device platforms that have been proven to be effective in heart failure. The CardioMEMS device (St. Jude Medical) is now approved, and is basically a pressure sensor that sits in the pulmonary artery and transmits information that the heart failure cardiologist uses to adjust medications. This device is easy to implant, and in many places, it is the heart failure physician who actually is doing the implant; in some hospitals, it is the interventional cardiologist. This is going to be an area of intersection, as some heart failure physicians retain training from their fellowship in doing simple procedures like right heart caths, and that is all that is required for the implantation of this particular device. There are other sensors in research that are a little bit more complicated to implant, for example, requiring an atrial septal puncture. I think a heart failure physician, even with invasive training, might not feel so comfortable doing a transseptal puncture and it would be another place for interventional cardiologists to come in, since that is now in their skill set. However, this class of devices is not really a therapy in and of itself, but it is a device that the physicians use to help optimize medical therapy. Nevertheless, it’s a very good example of something invasive that is helping these patients.

Who monitors and is responsible for that data? 

This remains a big challenge, because what happens is that the patient takes the readings at home and those are transmitted to a central database. At the central database, the data are being scanned by computer algorithms, and when certain abnormal conditions are met, meaning pressures are either too high or too low, an alert is sent to the clinic. As you can imagine, there are issues that need to be dealt with to handle these alerts: Who gets the alert? Who is responsible for contacting the patients and determining if an intervention is necessary? Are there false positive alerts? What about the issue of false negatives (i.e., not being alerted when something is actually going wrong)? So, management of these patients is proving to require significant attention from the clinic. The burden right now is falling on the heart failure doctors to figure out for themselves how to deal with this large amount of data. It is an issue that has not been resolved. This has resulted in a lower-than-expected penetration of these devices, especially when coupled with concerns from the hospital systems about who is going to pay for the labor required. Basically, it requires relatively skilled nursing at the minimum to deal with the massive amount of data that would be coming in, if a large number of patients in every clinic were to have these devices. So it remains unresolved, but is a very important issue.

b) Hemodynamic support in the setting of complex cardiac intervention

I think this is the field that has seen the most advances over the last several years. For decades, all we had was a balloon pump. Starting in the mid-to-late 90s, and really progressing very rapidly, we’ve had the introduction of several classes of devices, including the TandemHeart (CardiacAssist), the Impella (Abiomed), and what is referred to as ECMO, or extracorporeal advanced life support systems. These devices are primarily implanted by interventional cardiologists, and to a smaller degree, by heart failure specialists; surgeons are also involved, especially on the more invasive of these devices. While the use of these devices is proliferating extensively, I think there is still a lot of research to be done to understand which device should be used in what condition, and how to optimally manage the patients who are getting the different devices. Each class of device has its own physiology that underlies it, and also has its own set of hemodynamic effects in patients. The effect of the different devices depends on the underlying pathophysiology of the patient, which is also very complex and varied. The things that vary among patients are of course the degree of LV dysfunction, the degree of right ventricular (RV) dysfunction, the degree of pulmonary compromise, and the degree of fluid overload. Those are four of the major aspects, but there are still other concerns, such as the degree of renal dysfunction and the status of the autonomic nervous system. Many physicians do not have the appreciation that the effects of one device or another are different, depending on patient condition. It is a very complicated matter in terms of education and in terms of trying to standardize medical care. Therefore, what we do see is a wide range of clinical outcomes, not only in terms of morbidity, but more importantly, in terms of mortality. We don’t currently have the clinical trials to support the development of guidelines for the use of these devices. The acuity of the disease makes it difficult to do clinical research and has really delayed the development of more complete understanding and development of guidelines by the relevant societies. 

It sounds like we don’t necessarily need an evolution of the devices themselves, but more of an evolution of our understanding of how to use them.

I think it is a combination of both, actually, because the devices, as advanced as they have become, still have a ways to go in terms of reducing adverse events. In mechanical circulatory support, be it with acute or chronic devices, we can pump blood, but we have to continue to make it less invasive and therefore associated with less adverse events such as the bleeding and vascular complications. The complications are those faced by interventional cardiologists in their other procedures, including bleeding, vascular complications, stroke, and the development of atrial fibrillation. There is always room for more innovation and device improvement. However, as you suggested, the other part of the equation is definitely correct in that we don’t know, as a society, how to optimally use the devices that we have.

c) Stem cells and biologics

My comments on this topic tend to be polarizing, because I am of the belief that while these therapies hold great promise for the future, the basic science research is not yet to the point of truly supporting their clinical application. I think they represent a tremendous opportunity for the future, and our efforts now should really be focused in the preclinical arena. In the field of cell therapy, we know that very few (if any) of the cells that are injected survive very long. It’s been recognized that these cells have very little chance of developing into a contracting myocyte, and very little chance of directly contributing to contraction. As a result, the focus has shifted towards these cells producing paracrine effects and other secondary effects that may even be able to achieved without the cells themselves. I admit that as of now I am very extreme in my position. I participated in one of the earliest preclinical studies on the application of muscle precursor cells in animal studies and was underwhelmed with what I saw. Nothing that I have seen that has been published from others, either from the preclinical or clinical spectrum, has changed my position. Regarding gene therapy, I did have expectation that this had greater promise, primarily because there may be fewer hurdles to overcome. Not that this is an easy project, but I thought it would be simpler than cell therapy. However, there was an important negative gene therapy study reported recently, the CUPID study, which was a big setback for the field. From what I understand and am happy to know, however, is that the preclinical research is continuing in this realm. I think gene therapy does hold great promise for the future, particularly if additional breakthroughs can be demonstrated in the preclinical arena.

d) Evolution of left ventricular assist devices (LVADs)

One important goal for future innovation is minimization of LVADs and development of means for their implantation by interventional cardiologists. This has the potential to impact the treatment of end-stage heart failure the same way TAVR influenced treatment of aortic stenosis. The thought is to take a very sick patient with chronic heart failure, not necessarily the acute heart failure patient, but the chronic heart failure patient that needs a multi-year device, and to have VADs be miniaturized and developed to a point where they could be put in by an interventional cardiologist. I think this is still a very worthwhile goal. We were on track for development of such a device, but it ran into technological problems and then funding issues, so the project has been put on hold. New projects are in the works. But this, I think, will be the next big breakthrough. Putting durable LVADs in the hands of interventional cardiologists, along with an understanding of the role of the percutaneous mitral therapies in HFrEF, are really the biggest opportunities in interventional cardiology for heart failure. 

As we look ahead, do you envision any heart failure patients ever going right to intervention vs medication?

That is probably not possible or necessary. In other cardiovascular fields, you could imagine devices taking over and becoming first-line therapy, such as the treatment of hypertension. If some of the hypertension device-based therapies that we are looking at now can be proven effective and safe, it is possible to imagine that these devices would become first-line therapy over medicines, especially in certain socio-economic settings. However, in heart failure, these devices are always associated with significant adverse events, no matter how you cut it. The medicines we have nowadays are so effective that for a newly diagnosed patient with heart failure, medications are proven to be very safe when used properly and overseen by heart failure specialists. Medications have been shown to be very effective in reducing mortality and morbidity, reducing hospitalizations, improving symptoms, and improving quality of life. It would be hard to imagine any device that could achieve that kind of success with such a low adverse event profile for the newly diagnosed heart failure patient. So I think that devices will be relegated to the sicker population failing medical therapies. That is good news for patients, and I don’t think it is bad news for interventionalists or innovators, because the heart failure population is so large — approaching 6 million in the United States alone — that even with a 10% progression (which is probably a low estimate) into severe states over the course of a patient’s lifetime, per year, there are plenty of patients for interventional cardiologists to take care of, even if we have very effective and very safe devices. 

Dr. Juan F. Granada can be contacted at jgranada@crf.org. 

Dr. Daniel Burkhoff can be contacted at dburkhoff@crf.org.